Mechanisms of Resistance to Chimeric Antigen Receptor T Cell Therapy

Grace A Johnson; Frederick L Locke

doi:10.1016/j.hoc.2023.07.003

Mechanisms of Resistance to Chimeric Antigen Receptor T Cell Therapy

Hematol Oncol Clin North Am. 2023 Dec;37(6):1189-1199. doi: 10.1016/j.hoc.2023.07.003. Epub 2023 Aug 12.

Authors

Grace A Johnson¹, Frederick L Locke²

Affiliations

¹ University of South Florida Morsani College of Medicine, 560 Channelside Drive, Tampa, FL 336022, USA.
² H. Lee Moffitt Cancer Center, Department of Blood and Marrow Transplant and Cellular Immunotherapy, 12902 USF Magnolia Drive, Suite 3057, Tampa, FL 33612, USA. Electronic address: Frederick.locke@moffitt.org.

PMID: 37580193
DOI: 10.1016/j.hoc.2023.07.003

Abstract

CAR T cell therapy has significantly shaped the treatment landscape for refractory hematologic malignancies including large B-cell lymphomas, multiple myeloma, and leukemias. While response rates for a previously dismal prognosis have improved, certain obstacles still remain to achieving CAR T infallibility. In this article, we review the data surrounding proposed resistance mechanisms of tumors to CAR T, including the implications of target loss, exhausted T cells as effete effectors, the necessity of maximal CAR T expansion to durable response, the negative impact of an inflammatory milieu and a suppressive tumor microenvironment, and the optimal tumor-to-effector ratio that associates with best outcomes. The future of CAR T should aim to mitigate these weaknesses in order to bolster the efficacy of this revolutionary therapy.

Keywords: Acute lymphocytic leukemia; CAR T-cell therapy; Cellular immunotherapy; Chronic lymphocytic leukemia; Large B-cell lymphoma; Tumor microenvironment.

Publication types

Review